The design, synthesis, and biological evaluation of novel antitumor agents.

摘要

This dissertation is divided into four sections, and describes different aspects of anticancer drug design. The first section describes DNA alkylative systems based on aniline mustard agents. Nitrogen mustards which have the capacity to cross link to DNA have received widespread attention due to their potential as antineoplastic agents. In an effort to achieve selective cytotoxicity, a number of studies targeted at the hypoxic cell environment indicate the utility of aniline mustards which bear electron withdrawing functions. We have investigated the utility of the arene metal carbonyl group as an aniline mustard triggering device. The second section is concerned with the preparation of new classes of DNA intercalators. The preparation of the pyrrolo (9,10) phenanthrene nucleus is described. The utility of this template as a DNA intercalating drug delivery system is demonstrated by synthesis of derived bis-chloroethylamine alkylating system and a hybrid DNA interactive enediyne system. The third and fourth sections describe new results in enediyne chemistry and biology. In section three. the large scale preparation of new enediyne templates is described, together with the preparation of conjugates designed to immobilize DNA. The fourth section describes the preparation of cytotoxic enediynes which are targeted to hormone receptors, and their subsequent biological profiles. We have assembled discrete classes of enediyne hybrids where the enediyne pharmacophore is attached to an estrogenic delivery vehicle. This class of cytotoxic agents are designed to induce estrogen receptor lesions following diyl cyclization, and may become useful lead compounds for the arrest of Tamoxifen resistant tumors.;This dissertation describes the investigation of four independent classes of antitumor agents as described above. This work not only illustrates the synthesis of the compounds previously discussed but also shows their effectiveness by the various biological assays performed.